Remyelination protects neurons from DLK-mediated neurodegeneration.
DLK
Myelin
Myrf
c-Jun
demyelination
microglia
multiple sclerosis
neurodegeneration
oligodendrocyte
remyelination
Journal
bioRxiv : the preprint server for biology
Titre abrégé: bioRxiv
Pays: United States
ID NLM: 101680187
Informations de publication
Date de publication:
12 Oct 2023
12 Oct 2023
Historique:
pubmed:
24
10
2023
medline:
24
10
2023
entrez:
24
10
2023
Statut:
epublish
Résumé
Chronic demyelination is theorized to contribute to neurodegeneration and drive progressive disability in demyelinating diseases like multiple sclerosis. Here, we describe two genetic mouse models of inducible demyelination, one distinguished by effective remyelination, and the other by remyelination failure and persistent demyelination. By comparing these two models, we find that remyelination protects neurons from apoptosis, improves conduction, and promotes functional recovery. Chronic demyelination of neurons leads to activation of the mitogen-associated protein kinase (MAPK) stress pathway downstream of dual leucine zipper kinase (DLK), which ultimately induces the phosphorylation of c-Jun in the nucleus. Both pharmacological inhibition and CRISPR/Cas9-mediated disruption of DLK block c-Jun phosphorylation and the apoptosis of demyelinated neurons. These findings provide direct experimental evidence that remyelination is neuroprotective and identify DLK inhibition as a potential therapeutic strategy to protect chronically demyelinated neurons.
Identifiants
pubmed: 37873342
doi: 10.1101/2023.09.30.560267
pmc: PMC10592610
pii:
doi:
Types de publication
Preprint
Langues
eng
Subventions
Organisme : NINDS NIH HHS
ID : P30 NS061800
Pays : United States
Organisme : NINDS NIH HHS
ID : R01 NS120981
Pays : United States
Déclaration de conflit d'intérêts
T.S.S. and B.E. are co-founders of Autobahn Therapeutics, B.E. has received consulting fees from Autobahn Therapeutics and T.S.S. is a Senior Advisor to Autobahn Therapeutics.
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